Oral Treatment of Multiple Sclerosis By: Wen Wang, Brett Senay, Alex Ko, Aisha Abo Saada PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson Introduction: MS is a chronic progressive disorder Acute symptoms of demyelination, axonal transaction, and progressive neurodegeneration Results in long term disability The cause is largely unknown Pathophysiology: CNS inflammation and destruction of myelin sheath of neuron due to attacks by own immune system loss of oligodendrocytes Lesions in white matter Breakdown of axon of neurons Effected Population: Second leading cause of disability in young adults Females, born/raised far north and south in latitude, especially Scandinavian and northern European ethnicity Mostly females between 20-40, slightly older in males Treatment: No cure for MS Long term managed with immuno-modulating med, limit additions of new symptoms and prevent worsening Gilenya (Fingolimod) Reduces number of relapses Slows down physical progression of MS Dose: 0.5 mg, daily Cost: $31,000 per year – Covered by most private insurance plans How it Works Sphingosine-1-phosphate receptor modulator on lymphocytes Fingolimod phosphorylated (activated) by sphingosine kinase 2 Initially agonist, but results in internalization of receptors Receptor regulates the release of lymphocytes to the blood Side Effects Increased risk of infection Higher risk of infection from vaccines Blood pressure increase Macular edema Headaches Tecfidera (dimethyl fumarate) First approved by Health Canada in April 2013 Monotherapy for relapsing-remitting MS; reduces frequency of relapses and delays the progression of disability Half-life of the active metabolite is short (approx. 1 hour) May decrease lymphocyte counts Tecfidera (dimethyl fumarate) esterase dimethyl fumarate (DMF) monomethyl fumarate (MMF) Dimethyl fumarate is metabolized by esterases before reaching the systemic circulation to its primary active metabolite, monomethyl fumarate. Tecfidera (dimethyl fumarate) Nuclear Erythroid 2-Related Factor 2 (Nrf2) transcriptional pathway ARE: antioxidant response element GCLC: glutamate-cysteine ligase GSH: glutathione GstA2: glutathione S-transferase A2; HO-1: heme-oxygenase-1 Nqo1: NADPH quinone oxidoreductase 1 MMF: monomethyl fumarate Nrf2: nuclear factor erythroid-derived 2related factor 2 The Nrf2 pathway is involved in the cellular response to oxidative stress. Laquinimod Investigational agent proposed for relapseremitting MS Once daily immunomodulator Oral administration Laquinimod – Mechanism of Action Same MoA as Fingolimod Laniquimod is phosphorylated Modulates lymphocyte S1P (sphingosine-1phosphate) Prevents deployment of lymphocytes from lymphoid tissue which prevents autoimmune attack Crosses the blood-brain-barrier Laquinimod – Research 2 phase III trials (ALLEGRO & BRAVO) showed promise ALLEGRO & BRAVO prompted a third phase III trial (CONCERTO) Both studies showed a reduction on disability ALLEGRO showed an improvement in relapse rates Summary Slide Multiple sclerosis (MS) causes CNS inflammation and destruction of myelin sheath No cure for MS, treatments only slow down and delay worsening Fingolimod is phosphorylated by sphingosine kinase 2 – Mechanism of Action: Fingolimod phosphate internalizes the sphingosine-1phosphate receptor that mediates the release of lymphocytes from the lymph nodes The therapeutic effects of Tecfidera (dimethyl fumarate): – Mechanism of Action: appear to be mediated in part through the activation of the nuclear erythroid 2-related factor 2 (Nrf2) transcriptional pathway, which results in the upregulation of antioxidant response genes. Laquinimod – investigational agent similar to fingolimod but not yet approved by Health Canada, prevents deployment of lymphocytes from lymphoid tissue which prevents autoimmune attack References Cohen, J. et al. (2010). Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. New England Journal of Medicine, 362, 400-415. Multiple Sclerosis Society of Canada. Gilenya Frequently Asked Questions. Retrieved from http://mssociety.ca/en/treatments/treatments_updates_fingolimod.htm Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, Köhl J, Offermanns S, Wettschureck N, Schwaninger M. (2014). Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J Clin Invest. 24(5): 2188-92. Linker RA. (2011). Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 134: 678-92. Venci JV, Gandhi MA. (2013). Dimethyl fumarate (tecfidera): a new oral agent for multiple sclerosis. Ann Pharmacother. 47(12): 1697-1702. Rubin, Susan. (2013). Management of Multiple Sclerosis: An Overview. Disease a Month. 59: 253-260. Bruck, W., & Wegner, C. (2011). Insight into the mechanism of laquinimod action. Journal of the Neurological Sciences , 173-179. Chun, J., & Hartung, H.-P. (2010). Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis. Clinical Neuropharmacology , 91-101. Jeffery, S. (2012, 08 09). CONCERTO: A Third Phase 3 Trial for Laquinimod in MS .